Posttraumatic epilepsy (PTE) is a serious complication of traumatic brain injury (TBI), characterized by a latent period of months to years. This latent period suggests the initiation of injury-induced processes leading to a permanently epileptic brain. This proposal focuses on one fundamental consequence common to many forms of TBI: axonal injury. The hypothesis that axonal injury affects the activity of cell populations by triggering a slow axonal sprouting and formation of aberrant excitatory synapses, altering the balance of excitation and inhibition, and leaving the brain hyper excitable will be tested. There is previous evidence of injury-induced axonal sprouting by CA3 cells after Schaffer collateral transection, delayed hyperexcitability, and up-regulation of BDNF and trkB receptors. Is BDNF/trkB signaling necessary for the excessive excitability of PTE? Could an injury-induced up-regulation of BDNF signaling through trkB receptors contribute to the development of PTE by triggering axonal sprouting? Using a mouse model in which trkB receptors can be pharmacologically blocked, and applying neuroanatomical, molecular, and electrophysiological techniques, the hypotheses that sprouting of new axonal collaterals occurs after axonal injury in adult mice in vivo and requires trkB receptor activation, and that hyperexcitability after brain injury also requires trkB receptor activation will be tested. Elucidation of the role of trkB receptor signaling and axonal sprouting in hyperexcitabililty after TBI may provide novel therapeutic strategies to prevent posttraumatic epilepsy. PUBLIC HEALTH RELEVANCE: Roughly 1.4 million people suffer a traumatic brain injury (TBI) per year in the US and it is estimated that at least 5.3 million people currently have long-term disabilities from TBI, costing the economy billions of dollars (Thurman et al., 1999). Posttraumatic epilepsy (PTE) is one common long-term consequence of TBI. A unique feature of PTE is the characteristic prolonged latent period of months to years between the injury and the occurrence of the first seizure (Annegers et al., 1998; Agrawal et al., 2006), and its insensitivity to conventional antiepileptic treatments (Temkin, 2001). Therefore, to develop effective therapeutic strategies to minimize long- term consequences of TBI, it is essential that we better understand the occurrences during this latent period.